A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat

J.D. Mul; K. Nadra; N.B. Jagalur; I.J. Nijman; P.W. Toonen; J.J. Medard; S. Gres; A. de Bruin; G.S. Han; J.F. Brouwers; G.M. Carman; J.S. Saulnier-Blache; D. Meijer; R. Chrast; E. Cuppen

doi:10.1074/jbc.M110.197947

A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat

J.D. Mul, K. Nadra, N.B. Jagalur, I.J. Nijman, P.W. Toonen, J.J. Medard, S. Gres, A. de Bruin, G.S. Han, J.F. Brouwers, G.M. Carman, J.S. Saulnier-Blache, D. Meijer, R. Chrast, E. Cuppen

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

27 Citaten (Scopus)

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The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat model with a mutated Lpin1 gene (Lpin1(1Hubr)), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin1(1Hubr) rats are characterized by hindlimb paralysis and mild lipodystrophy that are detectable from the second postnatal week. Sequencing of Lpin1 identified a point mutation in the 5'-end splice site of intron 18 resulting in mis-splicing, a reading frameshift, and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity. Lpin1(1Hubr) rats developed hypomyelination and mild lipodystrophy rather than the pronounced demyelination and adipocyte defects characteristic of Lpin1(fld/fld) mice, which carry a null allele for Lpin1. Furthermore, biochemical, histological, and molecular analyses revealed that these lesions improve in older Lpin1(1Hubr) rats as compared with young Lpin1(1Hubr) rats and Lpin1(fld/fld) mice. We observed activation of compensatory biochemical pathways substituting for missing PAP1 activity that, in combination with a possible non-enzymatic Lipin 1 function residing outside of its PAP1 domain, may contribute to the less severe phenotypes observed in Lpin1(1Hubr) rats as compared with Lpin1(fld/fld) mice. Although we are cautious in making a direct parallel between the presented rodent model and human disease, our data may provide new insight into the pathogenicity of recently identified human LPIN1 mutations. [KEYWORDS: Alkylating Agents/pharmacology, Animals, Demyelinating Diseases/ enzymology/genetics/pathology, Ethylnitrosourea/pharmacology, HEK293 Cells, Humans, Introns, Lipodystrophy/ enzymology/genetics/pathology, Mice, Mutagenesis, Mutation, Phosphatidate Phosphatase/genetics/ metabolism, Protein Structure, Tertiary, RNA Splice Sites, Rats, Rats, Mutant Strains]

Originele taal-2	Engels
Pagina's (van-tot)	26781-26793
Tijdschrift	Journal of Biological Chemistry
Volume	286
Nummer van het tijdschrift	30
DOI's	https://doi.org/10.1074/jbc.M110.197947
Status	Gepubliceerd - 2011

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10.1074/jbc.M110.197947

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Mul, J. D., Nadra, K., Jagalur, N. B., Nijman, I. J., Toonen, P. W., Medard, J. J., Gres, S., de Bruin, A., Han, G. S., Brouwers, J. F., Carman, G. M., Saulnier-Blache, J. S., Meijer, D., Chrast, R., & Cuppen, E. (2011). A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat. Journal of Biological Chemistry, 286(30), 26781-26793. https://doi.org/10.1074/jbc.M110.197947

@article{80118c3761984dac918006990469b854,

title = "A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat",

abstract = "The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat model with a mutated Lpin1 gene (Lpin1(1Hubr)), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin1(1Hubr) rats are characterized by hindlimb paralysis and mild lipodystrophy that are detectable from the second postnatal week. Sequencing of Lpin1 identified a point mutation in the 5'-end splice site of intron 18 resulting in mis-splicing, a reading frameshift, and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity. Lpin1(1Hubr) rats developed hypomyelination and mild lipodystrophy rather than the pronounced demyelination and adipocyte defects characteristic of Lpin1(fld/fld) mice, which carry a null allele for Lpin1. Furthermore, biochemical, histological, and molecular analyses revealed that these lesions improve in older Lpin1(1Hubr) rats as compared with young Lpin1(1Hubr) rats and Lpin1(fld/fld) mice. We observed activation of compensatory biochemical pathways substituting for missing PAP1 activity that, in combination with a possible non-enzymatic Lipin 1 function residing outside of its PAP1 domain, may contribute to the less severe phenotypes observed in Lpin1(1Hubr) rats as compared with Lpin1(fld/fld) mice. Although we are cautious in making a direct parallel between the presented rodent model and human disease, our data may provide new insight into the pathogenicity of recently identified human LPIN1 mutations. [KEYWORDS: Alkylating Agents/pharmacology, Animals, Demyelinating Diseases/ enzymology/genetics/pathology, Ethylnitrosourea/pharmacology, HEK293 Cells, Humans, Introns, Lipodystrophy/ enzymology/genetics/pathology, Mice, Mutagenesis, Mutation, Phosphatidate Phosphatase/genetics/ metabolism, Protein Structure, Tertiary, RNA Splice Sites, Rats, Rats, Mutant Strains]",

author = "J.D. Mul and K. Nadra and N.B. Jagalur and I.J. Nijman and P.W. Toonen and J.J. Medard and S. Gres and {de Bruin}, A. and G.S. Han and J.F. Brouwers and G.M. Carman and J.S. Saulnier-Blache and D. Meijer and R. Chrast and E. Cuppen",

note = "Reporting year: 2011 Metis note: 3143639;",

year = "2011",

doi = "10.1074/jbc.M110.197947",

language = "English",

volume = "286",

pages = "26781--26793",

journal = "Journal of Biological Chemistry",

issn = "0021-9258",

publisher = "American Society for Biochemistry and Molecular Biology Inc.",

number = "30",

}

Mul, JD, Nadra, K, Jagalur, NB, Nijman, IJ, Toonen, PW, Medard, JJ, Gres, S, de Bruin, A, Han, GS, Brouwers, JF, Carman, GM, Saulnier-Blache, JS, Meijer, D, Chrast, R & Cuppen, E 2011, 'A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat', Journal of Biological Chemistry, vol. 286, nr. 30, blz. 26781-26793. https://doi.org/10.1074/jbc.M110.197947

TY - JOUR

T1 - A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat

AU - Mul, J.D.

AU - Nadra, K.

AU - Jagalur, N.B.

AU - Nijman, I.J.

AU - Toonen, P.W.

AU - Medard, J.J.

AU - Gres, S.

AU - de Bruin, A.

AU - Han, G.S.

AU - Brouwers, J.F.

AU - Carman, G.M.

AU - Saulnier-Blache, J.S.

AU - Meijer, D.

AU - Chrast, R.

AU - Cuppen, E.

N1 - Reporting year: 2011 Metis note: 3143639;

PY - 2011

Y1 - 2011

N2 - The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat model with a mutated Lpin1 gene (Lpin1(1Hubr)), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin1(1Hubr) rats are characterized by hindlimb paralysis and mild lipodystrophy that are detectable from the second postnatal week. Sequencing of Lpin1 identified a point mutation in the 5'-end splice site of intron 18 resulting in mis-splicing, a reading frameshift, and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity. Lpin1(1Hubr) rats developed hypomyelination and mild lipodystrophy rather than the pronounced demyelination and adipocyte defects characteristic of Lpin1(fld/fld) mice, which carry a null allele for Lpin1. Furthermore, biochemical, histological, and molecular analyses revealed that these lesions improve in older Lpin1(1Hubr) rats as compared with young Lpin1(1Hubr) rats and Lpin1(fld/fld) mice. We observed activation of compensatory biochemical pathways substituting for missing PAP1 activity that, in combination with a possible non-enzymatic Lipin 1 function residing outside of its PAP1 domain, may contribute to the less severe phenotypes observed in Lpin1(1Hubr) rats as compared with Lpin1(fld/fld) mice. Although we are cautious in making a direct parallel between the presented rodent model and human disease, our data may provide new insight into the pathogenicity of recently identified human LPIN1 mutations. [KEYWORDS: Alkylating Agents/pharmacology, Animals, Demyelinating Diseases/ enzymology/genetics/pathology, Ethylnitrosourea/pharmacology, HEK293 Cells, Humans, Introns, Lipodystrophy/ enzymology/genetics/pathology, Mice, Mutagenesis, Mutation, Phosphatidate Phosphatase/genetics/ metabolism, Protein Structure, Tertiary, RNA Splice Sites, Rats, Rats, Mutant Strains]

AB - The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat model with a mutated Lpin1 gene (Lpin1(1Hubr)), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin1(1Hubr) rats are characterized by hindlimb paralysis and mild lipodystrophy that are detectable from the second postnatal week. Sequencing of Lpin1 identified a point mutation in the 5'-end splice site of intron 18 resulting in mis-splicing, a reading frameshift, and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity. Lpin1(1Hubr) rats developed hypomyelination and mild lipodystrophy rather than the pronounced demyelination and adipocyte defects characteristic of Lpin1(fld/fld) mice, which carry a null allele for Lpin1. Furthermore, biochemical, histological, and molecular analyses revealed that these lesions improve in older Lpin1(1Hubr) rats as compared with young Lpin1(1Hubr) rats and Lpin1(fld/fld) mice. We observed activation of compensatory biochemical pathways substituting for missing PAP1 activity that, in combination with a possible non-enzymatic Lipin 1 function residing outside of its PAP1 domain, may contribute to the less severe phenotypes observed in Lpin1(1Hubr) rats as compared with Lpin1(fld/fld) mice. Although we are cautious in making a direct parallel between the presented rodent model and human disease, our data may provide new insight into the pathogenicity of recently identified human LPIN1 mutations. [KEYWORDS: Alkylating Agents/pharmacology, Animals, Demyelinating Diseases/ enzymology/genetics/pathology, Ethylnitrosourea/pharmacology, HEK293 Cells, Humans, Introns, Lipodystrophy/ enzymology/genetics/pathology, Mice, Mutagenesis, Mutation, Phosphatidate Phosphatase/genetics/ metabolism, Protein Structure, Tertiary, RNA Splice Sites, Rats, Rats, Mutant Strains]

U2 - 10.1074/jbc.M110.197947

DO - 10.1074/jbc.M110.197947

M3 - Article

SN - 0021-9258

VL - 286

SP - 26781

EP - 26793

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 30

ER -

A hypomorphic mutation in Lpin1 induces progressively improving neuropathy and lipodystrophy in the rat

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